Hypoglycemia in Type 2 Diabetes—Consequences and Risk Assessment
of action (5–15 minutes) compared with regular human insulin (30–60 minutes), higher peak action, and shorter duration of action, which more closely approximates endogenous mealtime insulin response, allowing more flexibility in the timing of meals and exercise and, consequently, a lower risk of HEs.71
Similarly, long-acting insulin
analogs exhibit a more consistent, longer, and flatter action profile than neutral protamine Hagedorn (NPH), and demonstrate a lower risk of hypoglycemia, particularly nocturnal.72–74
Advances in insulin therapy
continue to evolve, with newer insulins achieving a more physiological profile, ultimately resulting in a lower risk of hypoglycemia even when more intensive glycemic levels are targeted.
The incretin hormone, glucagon-like peptide-1 (GLP-1), is released by L-cells in the small intestine upon eating and induces glucose-dependent stimulation of insulin secretion while suppressing glucagon release. As a consequence of this glucose-dependent action, when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin, which minimizes the risk of hypoglycemia. GLP-1 is also associated with enhanced satiety, reduced food intake, and weight loss or neutrality; it may also preserve β-cell morphology and function. Incretin-based therapies include GLP-1 receptor agonists and dipeptidyl peptidase-IV (DPP-4) inhibitors. GLP-1 receptor agonists are resistant to degradation by DPP-4 and can be dosed to pharmacological levels. DPP-4 inhibitors block the enzyme that degrades incretin hormones, thereby increasing levels of intact, physiologically active endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) (see Figure 3).76
Recent advances in the treatment of type 2 diabetes have resulted in the development of incretin-based therapies which, through their glucose-dependent action, overcome some of the limitations of conventional treatments, including minimizing the risk of hypoglycemia and weight gain.75
Two GLP-1 receptor agonists have received US Food and Drug Administration (FDA) approval for treatment of type 2 diabetes. Exenatide is a synthetic mimetic of GLP-1, derived from the saliva of the Gila monster lizard, that shares 53 % amino acid sequence homology with human GLP-1. Liraglutide is produced by a chemical modification of native human GLP-1 and has 97 % homology to the human sequence.77,78
Figure 4 illustrates the possible mechanisms of
action of GLP-1 analogs, using liraglutide as an example. DPP-4 inhibitors approved by the FDA for use in type 2 diabetes include sitagliptin, saxagliptin, and linagliptin.79,80
Both classes of medications will
likely play more prominent roles in the management of type 2 diabetes as they provide effective glucose control, have a favorable weight profile (GLP-1 agonists lead to weight loss, DPP-4 inhibitors are weight-neutral), and have a low risk of hypoglycemia.59
Although therapeutic innovations in type 2 diabetes may help address the problem of poor glycemic control, improved communication between patients and caregivers is also a powerful tool that should be
1. Cryer PE, Axelrod L, Grossman AB, et al., Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab, 2009;94:709–28.
2. ADA, Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia, Diabetes Care, 2005;28:1245–9.
incorporated into current therapeutic approaches.81 There is a knowledge, attitude, and practice gap in type 2 diabetes. Many
patients do not understand HbA1c targets and how they can positively impact their long-term health. Patients struggle to meet lifestyle targets, especially those for weight control. Healthcare professionals can help patients in the self-management of diabetes by helping to create individualized approaches according to the needs, risks, and limitations of patients. Innovative strategies should be implemented that use a community-based approach to encourage diabetes self-management, and embrace new technologies that allow access to diabetes self-management education and support networks.82,83
A recent study evaluated the effect of intensive interventions involving weekly clinic visits, structured self-monitoring of glucose levels, patient education, and adjustment of therapy. There was a dramatic improvement in glycemic control within six weeks as measured by a
reduction in HbA1c of 1.82 ± 0.16 % versus 0.66 ± 0.22 % in the control group, which was sustained until Week 12. Additionally, there were no significant changes in the frequency of hypoglycemia or weight gain.84 Patient education should include such topics as self-monitoring blood glucose levels, and advice concerning nutrition and exercise. The routine discussion and assessment of hypoglycemia symptoms should be an important part of the regular review of patients with diabetes.85
Achievement of glycemic goals without risk of hypoglycemia, especially in patients with advanced diabetes, can only be accomplished if there is a close relationship between the patient and the healthcare team, with significant investment and commitment on the part of both. Patients should undergo intensive diabetes education with periodic refreshers, and the healthcare team should elicit at each visit a full history regarding all aspects of care, including: diet and its timing, treatment regimen and its timing, review of injection technique, if applicable, review of medication storage conditions and expiration dates, review of comorbidities, and new treatment regimens. If a patient is unable or unwilling to adhere to more intensive lifestyle and/or treatment recommendations, a more conservative glycemic goal with a larger ‘safety net’ for hypoglycemia should be considered.
Conclusion
Hypoglycemia has serious clinical, social, and economic consequences, and its occurrence in type 2 diabetes is likely to escalate along with the increase in disease prevalence, as more patients reach the insulin-defective stage of the disease. Hypoglycemia is not just the result of insulin use; in fact, most hypoglycemia is seen in patients using OADs. Treatment selection, as well as glycemic targets, should be customized based on each patient’s individual risk of hypoglycemia. Recent advances in diabetes therapy allow for lower blood glucose levels to be more intensively and successfully targeted, while reducing the risk of hypoglycemia. This should result in better adherence to therapy and improved clinical, health economics and QoL outcomes. n
3. CDA, Canadian Diabetes Association Clinical Practice Guidelines Expert Guidelines, Can J Diabetes, 2003;27(Suppl. 2):S43–S45.
4. EMEA, European Agency for Evaluation of Medicinal Products. Note for guidance on clinical investigations of medicinal products in the treatment of diabetes mellitus, 2006.
5. Handelsman Y, Mechanick JI, Blonde L, et al., American Association of Clinical Endocrinologists Medical Guidelines for
Clinical Practice for developing a diabetes mellitus comprehensive care plan, Endocr Pract, 2011;17(Suppl. 2):1–53.
6. Amiel SA, Dixon T, Mann R, Jameson K, Hypoglycaemia in Type 2 diabetes, Diabet Med, 2008;25:245–54.
7. Marks V, The measurement of blood glucose and the definition of hypoglycemia, Horm Metab Res, 1976;(Suppl. 6):1–6.
8. Service FJ, Dale AJ, Elveback LR, et al., Insulinoma: clinical and US ENDOCRINOLOGY 101
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84