Type 2 Diabetes: Sequencing Therapies
- Treatment of hyperglycemia in diabetes should be progressively intensified as necessary to control blood glucose to target ranges.
- Modification of cardiovascular risk factors and reduction in cardiovascular risk is equally important to reduce future cardiovascular events.
- This requires, first, establishing goals, especially for hemoglobin A1c and determining baseline cardiovascular disease status and risk. Patients without overt CVD, with shorter duration of disease, and lower baseline HbA1c may benefit from more intensive strategies. It then requires adjusting therapy to reach those targets.
- Recommendations should be considered in the context of the needs, preferences, and tolerances of each patient.
- Patient-centered care should be an organizing principle. It is defined as an approach to "providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions."
- Ultimately it is the patient that makes the final decisions regarding lifestyle choices.
- The risk of microvascular complications of diabetes (retinopathy, nephropathy, neuropathy) is closely related to control of blood glucose.
- Microvascular complications are a major cause of morbidity and mortality (see specific complications).
- Most people with diabetes do not have optimal glycemic control (average U.S. HbA1c >7%), indicating the need to advance therapy more quickly.
- Prevention of macrovascular complications (cardiovascular disease) has been historically linked to control of traditional risk factors (e.g. blood pressure, lipids, smoking), which should also be aggressively managed in people with diabetes.
- Since 2008, the Food and Drug Administration (FDA) set a requirement for new diabetes treatments to undergo additional trials focused on cardiovascular disease outcomes to demonstrate safety. Outcomes of these studies demonstrated superiority of specific agents compared to placebo, and led to some agents receiving FDA approval for cardiovascular risk reduction.
- Dietary modification and increased physical activity are always the basis of good care and have been shown in clinical studies to be more effective than medication in prevention of diabetes.
- It is important to individualize treatment goals. Shared decision making with the patient may help in selection of therapeutic options.
- Elements that can guide choosing an HbA1c target for a specific patient include: patient attitude and expected treatment benefits, risk potentially associated with adverse events (i.e. hypoglycemia), disease duration, life expectancy, comorbidities, functional status, established vascular complications, and psychosocial resources (i.e. support system).
- Metformin is generally the first-line oral agent (along with lifestyle recommendations) used in treating type 2 diabetes on diagnosis, unless contraindicated or not tolerated. Initially 500 mg one to two times daily (often started as once daily for 2-4 weeks to reduce gastrointestinal side effects) then titrated quickly. Maximize metformin dose to glycemic goals (unless GI side effects limit tolerated dose).
- Consider dual therapy if A1c is ≥1.5% above glycemic target. Should also initiate a second agent if glycemic control is inadequate on maximal doses of therapy (after 3 months).
- Current American Diabetes Association (ADA) and American Academy of Clinical Endocrinology (AACE) guidelines provide multiple options for additional therapy after metformin initiation.
- Some medications have received FDA approval for use in patients with diabetes beyond improving glycemic control. It is recommended that patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease include specific GLP-1 analogs or sodium-glucose cotransporter 2 inhibitors with demonstrated cardiovascular benefit as part of the treatment regimen. Some patients at high risk for cardiovascular disease may also benefit from newer agents with demonstrated cardiovascular benefit.
- GLP-1 analogs
- Approved to reduce the risk of major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors (primary or secondary CVD prevention).
- REWIND trial showed dulaglutide group had a 12% reduction in risk of MACE vs. the placebo group.
- Approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes and established cardiovascular disease
- LEADER trial showed a 13% reduction in composite death, nonfatal myocardial infarction, and nonfatal stroke versus placebo.
- Semaglutide (weekly injection only)
- Approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
- SUSTAIN 6 trial showed weekly semaglutide group had a 26% reduction in risk of major adverse cardiovascular event vs. placebo. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (including silent), or nonfatal stroke.
- Sodium-glucose cotransporter 2 inhibitors
- Approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
- CANVAS trial showed a 14% reduction in a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke versus placebo.
- Approved to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease
- EMPA-REG trial showed a 14% reduction in MACE and 38% relative risk reduction in death from cardiovascular causes versus placebo.
- Approved to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
- DECLARE trial showed dapagliflozin group had a 17% reduction in risk of cardiovascular death or hospitalization for heart failure than placebo. It should be noted that primary outcome in trial was driven by heart failure hospitalization as there was no difference in the rate of cardiovascular death.
- GLP-1 analogs
- Choices of additional agents recommended by ADA and AACE after metformin include (in no specific order):
- Sulfonylureas (high glucose-lowering ability, risk of hypoglycemia, weight gain, low cost)
- Thiazolidinediones (high glucose-lowering ability, weight gain, potential risk of HF, ASCVD-risk benefit, low cost)
- DPP-IV inhibitors (less likely to cause hypoglycemia and weight neutral)
- GLP-1 analogs (high glucose-lowering ability, weight loss, less likely to cause hypoglycemia, injectable)
- Early use of basal insulin (if A1c>8% on optimal therapy).
- Sodium-glucose cotransporter 2 inhibitor (less likely to cause hypoglycemia, promotes weight loss)
- Other approved agents to consider but less frequently used as additional oral agents include bromocriptine, colesevelam, alpha glucosidase inhibitors, and meglitinides.
- Review side effects and contraindications prior to initiating additional medications. Combination oral pills may be available.
- If patient is already on 2-3 oral agents and still not optimally controlled, consider adding a GLP-1 analog as the recommended initial injectable agent prior to initiation of insulin therapy in type 2 diabetes (T2DM) due to lower risk of hypoglycemia and potential weight loss. However, these agents may be more costly.
- Patients with high baseline HbA1c ( i.e. ≥10%) have a low probability of achieving a near-normal target with oral monotherapy. Insulin therapy may be initially considered on diagnosis. Once initial symptoms are resolved and metabolic state stabilized upon diagnosis, it may be possible to taper insulin partially or completely to non-insulin antihyperglycemic agents.
- In patients with new-onset diabetes, lifestyle therapy alone may be considered as initial therapy in a select group of patients with HbA1c close to goal (i.e. < 7.5%).
- Table Table 1 summarizes the relative efficacy of non-insulin glucose lowering agents available for the treatment of type 2 diabetes:
Percent reduction in HbA1c*
(Glyburide, Glipizide, Glimepiride)
Alpha Glucosidase Inhibitor
(Exenatide, Liraglutide, Dulaglutide, Semaglutide)
(Sitagliptin, Saxagliptin, Linagliptin, Alogliptin)
(Canagliflozin, Dapagliflozin, Empagliflozin)
Bile acid sequestrant
*Ranges are approximate and rounded to nearest half digit
- Changing treatment regimen may require follow-up more frequently than usual (i.e. review of weekly glucose logs), depending on the circumstance.
- At a minimum, patients with recent dose changes in therapy should be seen within 3 months in clinic; those on a stable regimen at goal may be seen at 6-month intervals.
- Consider dietary patterns and physical activity level when determining treatment regimen.
- Goals of care are to achieve glycemic targets but also avoid unacceptable hypoglycemia, improve quality-of-life, and also to reduce risk of cardiovascular disease.
- Many agents now have demonstrated cardiovascular benefit (i.e. a label indication from the FDA for reducing cardiovascular events) in patients with established cardiovascular disease, and in some instances, among those at high-risk for CVD; in patients with heart failure with reduced ejection fraction or CKD, specific SGLT2 inhibitors have also been found to have cardiovascular or renal benefit and are preferred in these patients.
- The most common error in blood glucose management is advancing treatment regimen too slowly, allowing prolonged poor glycemic control.
- Beware of "clinical inertia": the tendency of clinicians not to change a medical regimen even when it is not working after some time.
- The progressive nature of type 2 diabetes and need for intensification of therapies should be explained to patients.
- Avoid using insulin as a threat or describing it as a failure of treatment.
- When initiating insulin, consider continuation of another agent if appropriate (e.g. metformin) to potentially reduce insulin requirement and weight gain.
- T2DM often requires multiple oral agents and/or relatively high-dose insulin therapy.
- Wide differences exist among clinicians’ exact sequencing of oral agents; evidence favoring one sequence over others is virtually nonexistent especially after initiation of metformin among those without history of cardiovascular disease, heart failure, or CKD.
- A patient-centered approach be used to guide the choice of pharmacological agents.
- Considerations in choosing therapies include efficacy, cost, potential side effects, effects on weight, cormobidities, hypoglycemia risk, and patient preferences.
- Alpha glucosidase inhibitors may also be beneficial for dumping syndrome in patients after gastric bypass surgery
- Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. [PMID:31189511]
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. [PMID:30415602]
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. [PMID:28605608]
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. [PMID:27295427]
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. [PMID:27633186]
- 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 American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-9. [PMID:25538310]
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. [PMID:26378978]
- Nathan DM, Buse JB, Davidson MB, et al. 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(1):193-203. [PMID:18945920]
Comment: A concensus committee's recommendation on sequencing of treatment of type 2 diabetes. Quite non-specific after initiation of metformin.
- Bolen SD, Bricker E, Samuels TA, et al. Factors associated with intensification of oral diabetes medications in primary care provider-patient dyads: a cohort study. Diabetes Care. 2009;32(1):25-31. [PMID:18931096]
Comment: An interesting study of factors that contribute to "clinical inertia", the tendency not to adjust treatment even when it is not working.
- Mooradian AD, Bernbaum M, Albert SG. Narrative review: a rational approach to starting insulin therapy. Ann Intern Med. 2006;145(2):125-34. [PMID:16847295]
Comment: A useful review of available insulins and a practical consideration of how to start and then intensify insulin regimens
- Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143(8):559-69. [PMID:16230722]
Comment: Open label comparison of exenatide (an incretin mimetic) vs. insulin glargine in type 2 diabetics who had failed oral agents. Exenatide had similar glycemic efficacy, but more weight reduction, and higher incidence of gastrointestinal side effects.
- Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106-18. [PMID:15356308]
Comment: An important review of the mechanisms of action, side effects and clinical use of thiazolidinediones.
- Klein S, Sheard NF, Pi-Sunyer X, et al. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care. 2004;27(8):2067-73. [PMID:15277443]
Comment: An expert committee statement of the rationale and approaches to weight control.
- Miller CK, Edwards L, Kissling G, et al. Nutrition education improves metabolic outcomes among older adults with diabetes mellitus: results from a randomized controlled trial. Prev Med. 2002;34(2):252-9. [PMID:11817922]
Comment: A relatively small randomized trial in which patients were given nutrition education or not. Those educated in a sound nutrition plan showed better glycemic control.
- Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403. [PMID:11832527]
Comment: The Diabetes Prevention Program demonstrated that Intensive Lifestyle reduced incidence of diabetes by 58%, metformin by 31% in subjects with impaired glucose tolerance
- Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13 Suppl 1:1-68. [PMID:17613449]
Comment: AACE Clinical Guidelines for managing diabetes, describing in detail the available medications available, important characteristics, and a general statement of choices for sequencing.
- Jellinger PS, Davidson JA, Blonde L, et al. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007;13(3):260-8. [PMID:17599857]
Comment: AACE statement of recommended sequencing on treatments.
- American Diabetes Association: Standards of medical care in diabetes--2017. Diabetes Care Vol 40 Suppl 1. https://professional.diabetes.org/sites/professional.diabetes.org/files/me...
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