Type 2 Diabetes: Sequencing Therapies

Erica Hall, MSN, ANP-BC, CDE, Rita Rastogi Kalyani, M.D., M.H.S., Christopher Saudek, M.D.


  • Treatment of hyperglycemia in diabetes should be progressively intensified as necessary to control blood glucose to target ranges.
  • This requires, first, establishing goals, especially for hemoglobin A1c and avoidance of unacceptable hypoglycemia.
  • 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."[1]
  • Ultimately it is the patient that make the final decisions regarding their lifestyle choices; their implementation occurs in the context of patients’ day-to-day life.


  • 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) is more closely linked to control of traditional risk factors (blood pressure, lipids, smoking), which should also be aggressively managed in people with diabetes.
  • Patients without overt CVD, with shorter duration of disease, and lower baseline HbA1c may benefit from more intensive strategies.


  • 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[9].
  • 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: generally first-line oral agent in treating type 2 diabetes along with lifestyle recommendations on diagnosis, unless contraindicated or not tolerated. Initially 500 mg two to three 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)
  • Current ADA and American Academy of Clinical Endocrinology (AACE) guidelines provide multiple options for additional therapy after metformin initiation.
  • Add a second oral agent if glycemic control is inadequate on maximal doses of therapy (after ~3 months)
  • Choices of additional agents after metformin include (in no specific order):
    • Sulfonylureas (relatively potent glucose-lowering agents)
    • Thiiazolidinediones (with additional benefits on lipids and less likely to cause hypoglycemia)
    • Metaglinides (for postprandial hyperglycemia)
    • Alpha glucosidase inhibitor (for postprandial hyperglycemia)
    • DPP-IV inhibitor (less likely to cause hypoglycemia and weight neutral)
    • Injectable GLP-1 analog such as exenatide (often causes weight loss and less likely to cause hypoglycemia)
    • Early use of basal insulin (if A1c>8%).
  • Other recently approved agents for diabetes to consider as additional oral agents include bromocriptine, cholesevelam, and canagliflozin
  • Review side effects and contraindications prior to initiating additional medications. Combination oral pills may be available.
  • Ideally, consider initiation of insulin therapy in type 2 diabetes (T2DM) if patient already on 2-3 oral agents and still not optimally controlled.
  • 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%)[1]
  • Maximum benefit for all glucose lowering agents observed with monotherapy versus add-on-therapy.
  • Table Table 1 summarizes the relative efficacy of non-insulin glucose lowering agents available for the treatment of type 2 diabetes:
Table 1

Percent reduction in HbA1c*





(Glyburide, Glipizide, Glimepiride)



(Pioglitazone, Rosiglitazone)



(Repaglinide, Nateglinide)


Alpha Glucosidase Inhibitor

(Acarbose, Miglitol)


Amylin Analog



GLP-1 Analog

(Exenatide, Liraglutide)


DPP-4 Inhibitor

(Sitagliptin, Saxagliptin, Linagliptin, Alogliptin)


SGLT2 Inhibitor

(Canagliflozin, Dapagliflozin, Empagliflozin)


Dopamine agonist



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.


  • Goal is to achieve glycemic targets but also avoid unacceptable hypoglycemia.
  • 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[3].
  • 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 an oral agent if appropriate (i.e. 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.
  • The American Diabetes Association has recommended that 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 preference.
  • Alpha glucosidase inhibitors may also be beneficial for dumping syndrome in patients after gastric bypass surgery


  1. 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]
  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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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Last updated: August 1, 2017