Glycemic control in type 2 diabetes-how low should you go?
Treatment of the whole patient is key and should include management of dyslipidemia, weight, and hypertension, as well as blood sugar.
Recent updates to the
Current guidelines for glycemic control in T2DM
The recently updated 2015 ADA/EASD guidelines recommend an A1C goal of <7% for most patients, with a more stringent goal of A1C <6.5% reserved for carefully selected patients, if achievable without adverse e ects, including hypoglycemia.3 The 7% threshold is based on data from the Diabetes Control and Complications Trial (DCCT), which showed that diabetic complications such as retinopathy, nephropathy, and neuropathy can be reduced with intensive glycemic control.4 A less stringent control is suggested for patients with speci c characteristics, such as limited life expectancy, history of severe hypoglycemia, advanced micro- or macrovascular complications, and/or other comorbidities.3
According to
How low should we go?
The 2015 ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes advocates a more patient-centered approach, determining whether to use more stringent or less stringent glycemic control, based on factors such as age and established cardiovascular risk.2 According to
In agreement, Dr. Zonszein a^ rms the importance of bringing A1C down to normal levels in the patient with early diabetes who is young, healthy, and without comorbidities, adding that when A1C is lowered to within normal range with medications that do not induce hypoglycemia or weight gain, "Both fasting and postprandial blood sugar oscillations are much more narrow, there is less oxidative injury and mitochondrial damage,7 and fewer complications." Dr. Zonszein adds that there is confusion among primary care providers with the shift toward patient-centered glycemic control and targeting di^erent A1C levels in di^erent patients. "I think primary care providers want real guidance, want a real recipe, and what the ADA has done is to move away from a 'one-size-^ts-all' type of recipe using set medications and A1C levels in di^erent types of patients."
According to
Dr. Zonszein agrees: "Primary care providers were pushed by the insurance companies, by the hospitals, by everybody to bring the A1C much lower and, as a result of that, we are seeing a lot of hypoglycemia, especially in the elderly."8 He notes that the elderly population often lacks awareness of hypoglycemia.
Dr. Zonszein adds, "When we see somebody ending up in the ED with a low blood sugar, they are likely to have been living with a low blood sugar for weeks before the ED visit. So we have to know how to treat each patient individually. And again, the ADA guidelines are very good, but there are pros and cons of targeting A1C."
A1C lowering: the method matters
"The other point is not where the A1C is but how we bring it down, and I think that is very critical," states Dr. Zonszein, noting that the DCCT trial showed that intensive glycemic control, resulting in a mean A1C <7%, reduced microvascular complications of diabetes in patients with type 1 diabetes.4 "So we try to lower A1C to below 7% to avoid these complications, but again, how are we going to lower the A1C? And in which patients? The majority of patients are being treated with what I call 20th century medications: insulin, sulfonylurea, and metformin. But very few patients, especially among the elderly, are being treated with 21st century medications, such as dipeptidyl peptidase-4 (DPP-4s) inhibitors, glucagon-like peptide (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. These medications can lower the blood sugar quite significantly, but without hypoglycemia and without weight gain, and sometimes they help the patient to lose weight and/or improve blood pressure." Dr. Zonszein points out the importance of taking into account comorbidities, age, antecedent hypoglycemia, polypharmacy, and current A1Clowering therapy when determining how to treat patients. "Everything is a factor in how we treat patients," he observes.
Individualizing beyond A1C
In 1987, at the annual
Dr. Zonszein states that patients who are diagnosed with prediabetes or diabetes "have lost much more than 50% of their beta cell function, probably 80%,11 depending on how you measure it." The most important contributor to apoptosis or death of the beta cells tends to be hyperglycemia, often described as glucose toxicity, according to Dr. Zonszein. He adds that, of the many likely contributors, even small oscillations of blood sugars contribute to beta cell apoptosis (death).14 It is important to treat patients early and aggressively, observes Dr. Zonszein. "I have to say that when we treat diabetes, we don't only treat 'blood sugars,' we treat patients as a whole, addressing obesity, dyslipidemia, and hypertension." Dr. Zonszein cites the STENO 2 trial, which reported a 50% reduction in the risk of cardiovascular and microvascular events with use of an intensive, multifactorial intervention-as compared with a conventional intervention-to address modifiable risk factors, such as glucose, lipids, and blood pressure.15 He states that normalizing cholesterol with a statin "is 80% of the treatment we are doing for cardiovascular disease in patients with type 2 diabetes."
Combination therapy and hypoglycemia risk
In his own practice, Dr. Zonszein starts with combination therapy early in the disease, often at the time of diagnosis. "I think when we use combination therapy, we have a better impact on blood sugar control and end up needing less medications long term," he states. "If I use combination therapy without a hypoglycemic agent (such as insulin and/ or insulin secretagogues), patients do not need to monitor their blood sugars three to five times a day, while A1C is being lowered. So the importance of using 21st century versus 20th century medications is huge. It is important for managing early diabetes, and particularly important in the elderly population in order to avoid hypoglycemia."
Recalling the 2009 Banting Lecture, in which DeFronzo reported an 80% to 85% loss of beta cell function in the upper tertiles of impaired glucose tolerance,11
It is important,
Dr. Zonszein adds that health care providers must also account for tremendous variability in patient response, noting that diabetes management involves trial and error. "When we look at clinical trials and see the A1C changes, it is done in a selectively chosen population for clinical studies, but in clinical practice I have seen a tremendous variability, with some not responding, while others having a more dramatic change in the A1C and/or weight than those reported in the clinical trial. In choosing a medication and/or combination therapy, it is important to look at the patient as a whole-obtain a good history and physical examination, look at the phenotype to see whether or not there is central obesity. For instance, I do not manage blood sugars without looking at the lipids. Patients with a high HDL are more insulin-sensitive, whereas patients with a very low HDL-as we often find with the metabolic syndrome-tend to be very insulin resistant."
Dr. Zonszein adds that in his practice, he uses a patientcentered approach, tailoring medications for each patient and emphasizing therapeutic dietary and exercise regimens. Despite the fact that diabetes is relatively common, he adds, long-term combination therapy studies are lacking, and primary care providers are hesitant to start with combination therapy due to the lack of trials to support such an approach. Dr. Zonszein believes that clinicians need "to use the art of medicine and decide what type of medication is better for what type of patient and what type of combination therapy is better for each patient." He points out that the GRADE trial is a long-term combination trial that will be evaluating the combinations of metformin with sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and insulin glargine.23 "We already suspect which of these combination treatments will be more effective, but we will need to wait five years to see which is more effective, and which causes more weight gain and hypoglycemia."
Early intensive therapy
Dr. Zonszein adds that, in general, "Metformin is underprescribed and underutilized in prediabetic patients, and often even in patients with the diagnosis of diabetes."
The United Kingdom Prospective Diabetes Study (UKPDS) 2624 and UKPDS 4925 looked at A1C control with the use of sulfonylureas, metformin, or insulin. These studies demonstrated that after initial improvement in A1C, there was a progressive and inexorable decline in beta cell function, regardless of whether patients were treated with diet alone, metformin, or sulfonylureas.24,25 In the Whitehall II trial, Tabak and colleagues demonstrated that insulin resistance and decline in beta cell function are established up to 13 years before the time of diagnosis,26 "and the progression of the disease does not stop," warns
In his current practice,
Health care providers may be confused by results of intensive therapy trials. The Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) trial30 showed a 42% reduction in cardiovascular disease and a 57% reduction in risk of nonfatal myocardial infarction, stroke, and death from cardiovascular disease with intensive therapy, as compared with conventional therapy, in patients with type 1 diabetes. Similarly in the UKPDS, the intensively treated arm of the study showed early decrease of microvascular complications, but long-term data showed decreased cardiovascular disease 10 years later in those treated more aggressively, with 15% decreases in myocardial infarction (P = .01) and 13% decrease in all-cause mortality (P =.007). In the subpopulation treated with metformin, even more favorable outcomes were observed (33%, P = .005, and 27%, P = .002 respectively.)31
More recently, a meta-analysis of intensive therapy studies in patients with type 2 diabetes showed that with early, aggressive insulin therapy, 42.1% of patients achieved glycemic remission without antidiabetic drugs for two years.32 "When I saw this published several times, I started using aggressive insulin management to reverse the glucose toxicity along with lifestyle changes to reduce the carbohydrate burden in my patients, and they were normalizing," states
Dr. Zonszein states, "I use insulin in patients with type 2 diabetes when they are catabolic, losing weight and have the typical symptoms of polyuria, polyphagia, and polydipsia. It works well." He cites a study by Weng and colleagues,33 in which use of aggressive insulin therapy very early in diabetes was shown to normalize blood sugar and improve beta cell function. "This is not uncommon, and is often the result of treating 'glucose toxicity.' It can happen with diet alone, with insulin, or with any of the oral agents. Patients need to understand that when they are diagnosed to have diabetes they already have 'sick beta cells,' thus once they have diabetes, they always have diabetes even if they are well controlled."
Echoing
Barriers to newer approaches
The need for patient and provider education. According to Dr. Zonszein, many patients dislike taking medications and will delay starting them and/or stop taking them once they see that their A1C is normal. Patient education is therefore crucial. In addition to patient education, Dr. Zonszein states, "We also need professional education for the providers, because I find that some of them actually are afraid of lowering the A1C to 6.0 or 5.5." Dr. Zonszein attributes these fears to results of the cardiovascular outcomes in studies such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD).34 However, in all other studies such as the DCCT/EDIC, UKPDS, ADVANCE, and VADT, the intensively treated arm resulted in better outcomes.4,31,35,36
The ACCORD, ADVANCE, and VADT trials were conducted in patients who had had diabetes for 8 to 10 years and already had diabetic complications. "These 3 studies showed that in patients who have lived for 8 or 10 years with an elevated A1C, lowering blood sugar to a normal level did not make a tremendous difference in cardiovascular mortality," Dr. Zonszein explains, adding that in ACCORD, there was increased total mortality that was not caused by hypoglycemia.31,34,35,37 The cause is still unexplained, but many providers have used the study findings as an excuse not to be more stringent in individuals who are young and without comorbidities. With patients such as those in the ACCORD trial, with untreated or poorly treated diabetes for 8 to 10 years, it is "Too much, too late," according to Dr. Zonszein. Again, as
Studies with early intervention, such as the DCCT/EDIC4,30 or the
The need for simplified regimens. "Insulin treatment use in patients with type 2 diabetes has gone up significantly," Dr. Zonszein points out. Because prior approval is often not required for prescribing insulin, many providers elect to use insulin instead of prescribing other agents that require prior approval, such as incretins, DPP-4 inhibitors, GLP receptor analogues, and/or SGLT2-inhibitors. Dr. Zonszein refers to these newer agents as "21st century antidiabetic medications," noting that even though 5 GLP-1 receptor analogues are approved for use in the US, 3 of which are injected weekly, these drugs are still not commonly used.
"We do have a good armamentarium with which to treat patients nowadays, but the cost and/or need for prior approval are important limiting factors," Dr. Zonszein states. The "prior approval" process, says Dr. Zonszein, is one of the critical reasons health care providers do not prescribe newer medications. The other part of the problem is that while it is very easy to prescribe insulin regimens, it is very hard for patients to adhere to these regimens and to titrate the proper insulin dose. In order to titrate the dose, patients need to measure their blood sugar several times a day, and they rarely do it. As a result, the provider prescribes a fixed dose of prandial insulin to be taken regardless of the meal size and/or caloric content. In his practice, Dr. Zonszein has observed that when he recommends four injections daily, "if they take two injections a day, I am lucky. Also, patients do not take their insulin if their blood sugars are normal, and when their blood sugars are high they take more insulin, creating a 'yo-yo' effect that results in elevated A1Cs and also hypoglycemic events that require hospitalizations."
New agents for glycemic control
It is important to remember, according to Dr. Zonszein, that there are now GLP receptor analogues, DPP-4 inhibitors, and SGLT2 inhibitors which are very effective agents in treating prandial hyperglycemia. Further, these agents do not require dose titration to be effective. "We are using more and more combinations of metformin, a GLP analogue, and basal insulin," in order to achieve the ideal trifecta in diabetic treatment-glycemic control, low risk of hypoglycemia, and low risk of weight gain.39 This type of combination therapy has shown to be associated with fewer hospitalizations and lower total-all cause health care costs when compared to basal bolus insulin regimens.40 "So we don't have to use bolus or prandial insulins as much as before in patients with type 2 diabetes; we can combine a basal insulin with a GLP analogue or SGLT2 inhibitor, often with better results, with less hyopoglycemia, less weight gain and often weight loss. It is easier for the patient and provides a better quality of life with more effective glycemic control."
The new class of SGLT2 inhibitors, included in the 2015 ADA/EASD position statement,2 work by reducing sodium glucose reabsorption in the kidney, independently of the presence of beta cell function and liver function.2 "They provide an advantage in the management of type 2 diabetes, not only because of the low risk of hypoglycemia but also because these agents also address the glycemic burden to the body,"
Possible side effects with SGLT2 inhibitors include genital mycotic infections, urinary tract infections, and volume depletion; thus, caution is advised in the elderly.2 According to the recent 2015 ADA/EASD recommendations, "The major change in the treatment options since the publication of the 2012 position statement has been the availability of a new class of glucose-lowering drugs, the SGLT2 inhibitors. Given their demonstrated efficacy and clinical experience to date, they are reasonable options as a second- or third-line therapy."
"I think we have a lot of tools available to us in managing diabetes,"
Conclusion
In conclusion,
The 2015 ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes advocates a more patient-centered approach.
"Primary care providers were pushed by the insurance companies...to bring the A1C much lower."-Joel Zonszein, MD, CDE, FACE, FACP
It is important to take into account comorbidities, age, antecedent hypoglycemia, polypharmacy, and current A1C-lowering therapy when treating patients.
Results from the EDICT trial support the use of combination therapy early in the management of patients with diabetes.
Primary care providers are hesitant to start with combination therapy due to the lack of trials to support such an approach.
A meta-analysis showed that with early, aggressive insulin therapy, 42.1% of patients achieved glycemic remission without antidiabetics for two years.
GLP receptor analogues, DPP-4 inhibitors, and SGLT2 inhibitors are very effective agents in treating patients with prandial hyperglycemia.
Providers are encouraged to use anti-diabetic therapies more aggressively and introduce combination therapy with newer agents earlier.
References
1. Inzucchi SE, Bergenstal RM, Buse JB; Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of the
2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the
3. American Diabetes Association Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(Supplement 1):S1-S94.
4.
5. Garber AJ, Abrahamson MJ, Barzilay JI, et al;
6. Nathan DM, Kuenen J, Borg R, et al;
7. Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: The "metabolic memory": is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab. 2009;94(2):410-415.
8. Lipska KJ, Ross JS, Wang Y, et al. National trends in US hospital admissions for hyperglycemia and hypoglycemia among
9. Monnier L, Lapinski H, 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 HbA(1c). Diabetes Care. 2003;26(3):881-885.
10. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. 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(11):3080-3086.
11. 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(4):773-795.
12. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6):667-687.
13. Del
14. Wali JA, Masters SL, Thomas HE. Linking metabolic abnormalities to apoptotic pathways in beta cells in type 2 diabetes. Cells. 2013;2(2):266-283.
15. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.
16. Esposito K, Ciotola M, Maiorino MI, et al. Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial. Ann Intern Med. 2008;149(8):531-539.
17. 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(6):386-399.
18. Simeone JC, Quilliam BJ. Predictors of emergency department and outpatient visits for hypoglycemia in type 2 diabetes: an analysis of a large US administrative claims database. Ann Pharmacother. 2012;46(2):157-168.
19. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154(9):602-613.
20.
21. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131(4):281-303.
22. Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA . Initial combination therapy with metformin, pioglita zone and exenatide is more ef fec tive than sequential add -on therapy in subjec ts wi th new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Ther apy for Type 2 Diabetes (EDICT ): a randomized trial. Diabetes Obes Metab. 2014. doi: 10.1111/dom.12417. [Epub ahead of pr int]
23. Nathan DM, Buse JB, Kahn SE, et al;
24. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years.
25. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49).
26. Tabák AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimäki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373(9682):2215-2221.
27. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51(9):2796-2803.
28. Kahn SE, Lachin JM, Zinman B, et al;
29. Levin D, Bell S, Sund R, et al; on behalf of the
30. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of
31. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
32. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013 Sep;1(1):28-34.
33. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on betacell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753-1760.
34. Action to Control Cardiovascular Risk in
35. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139.
36. The Action in Diabetes and Vascular Disease:
37. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.
38. AID Program, 2015, http://www.accurateinsulin.org/. Accessed
39. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228-2234.
40. Dalal MR, Xie L, Baser O, DiGenio A. Adding rapid-acting insulin or GLP-1 receptor agonist to basal insulin: outcomes in a community setting. Endocr Pract. 2015;21(1):68-76.
EDITORIAL: Residents should take earthquake drill seriously
Advisor News
Annuity News
Health/Employee Benefits News
Life Insurance News