Medication Selection for Type 2 Diabetes

Educational Objectives

The goal of this program is to improve the management of patients with diabetes mellitus (DM). After hearing and assimilating this program, the clinician will be better able to:

1. Implement recommendations from the American Diabetes Association algorithm for treatment of DM.
2. Cite current literature regarding available agents for the treatment of DM.
3. Recognize the association between DM and cardiovascular disease.

Summary

Latest diabetes mellitus (DM) treatment algorithm (American Diabetes Association [2020]): in patients with established vascular disease or indicators for high risk (eg, age ≥55 yr with coronary, carotid, or lower extremity artery stenosis), preferable to use a glucagon-like peptide 1 (GLP-1) agonist or a sodium-glucose cotransporter-2 (SGLT2) inhibitor; in patients with heart failure (HF) or kidney disease, the preference after metformin is an SGLT2 inhibitor, which can be replaced by a GLP-1 agonist if contraindicated or not tolerated; if cardiovascular disease (CVD), HF, or kidney disease are not the compelling issues and the goal is to improve blood sugars while limiting the risk for hypoglycemia, metformin is the first choice, followed by a dipeptidyl peptidase-4 (DPP-4) inhibitors (probably the weakest drug in the group, less effective for glucose lowering), GLP-1, SGL2, or thiazolidinedione (TZD); if targets are not met, add a different drug; the same options are recommended for minimizing weight gain and promoting weight loss; if cost is an issue, after metformin consider sulfonylurea (SU) or TZD; add a new drug or consider insulin if targets are not met

DM and CVD: 75% of patients with DM have hypertension; 2- to 4-fold increased risk for stroke, 2-fold increased risk for CVD death, and 2- to 4-fold higher hospitalization for CVD compared with patients without DM; the largest group are patients with congestive heart failure (CHF); in 2008, the Food and Drug Administration (FDA) released new guidelines requiring all new diabetes drugs to undergo ongoing evaluation for increased cardiac risk; this was related to safety issues with rosiglitazone, the ACCORD trial, and another drug that was dropped <1 wk after coming to market because of concerns about increased cardiovascular (CV) risk; DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 agonists have undergone such safety evaluations

CV outcome trials: most are phase 4 trials; outcomes are usually 3-point major adverse cardiac event (MACE; eg, CV death, nonfatal myocardial infarction, nonfatal stroke); 4-point trials add hospitalization for unstable angina; 5-point trials add hospitalization for CHF; key item in all these studies is glycemic equipoise; intent is to evaluate safety, not to change glucose management; among patients hospitalized for HF, the prevalence of DM is >40%

Metformin: remains the generally recommended first drug because it has been used for decades, is inexpensive, and clinicians are aware of the side effects; speaker believes it will not be the first drug of choice in the near future; patients on metformin who develop CHF have a reduced risk for death, hospitalization for CHF, and hospitalization for any cause; multiple studies have shown patients taking metformin as a single drug have lower incidences of HF and CV death compared with SU; meta-analyses dating back to 2008 showed metformin was associated with a significant decrease in CV mortality; in patients with reduced kidney function, metformin was associated with reduced CV mortality and morbidity compared with SU; Apolzan et al (2019) compared lifestyle interventions, metformin, and placebo for weight loss in patients with prediabetes; weight change was initially best with lifestyle compared with metformin; incidence of DM was best with lifestyle; patients with the best weight loss over 15 yr were those on metformin with good weight loss initially

Sulfonylureas: Ke et al (2017) found that among South Asian and Chinese patients in Canada, mortality and MACE were higher in patients on SUs; widespread use of SUs signalled an increase in mortality for all patients; SUs increase risk for hypoglycemia; patients with hypoglycemia experience more cardiac changes; Middleton et al (2017) detected hypoglycemic episodes in 9 out of 30 patients with type 2 DM (T2DM) taking SUs; episodes were primarily nocturnal and asymptomatic, and were associated with QT prolongation and QT dynamicity (poor prognostic sign for CVD); trend toward increased ventricular and supraventricular ectopy did not achieve statistical significance; meta-analysis by Azoulay et al (2017) showed SUs were associated with increased risk for CVD and mortality; some concern that metformin lowers CV risk, as opposed to SUs increasing risk; Rosenstock et al (2019) found no difference in CV risk when linagliptin and glimepiride were compared; currently awaiting data from a more definitive study; SUs are low cost and may be acceptable, especially in combination with other drugs that alter CV risk; currently no evidence SUs are beneficial

Thiazolidinediones: reduce glucose levels, albuminuria, and non-alcoholic steatohepatitis but cause weight gain (blunted with metformin and worsened with insulin); may cause edema unresponsive to diuretics in ≤30% of patients; provide potential CV benefits; Dormandy et al (2005) showed addition of pioglitazone to standard treatment was associated with a 10% reduction in adverse CV outcomes; Kernan et al (2016) investigated pioglitazone in patients with insulin resistance, but not DM, who had a stroke or transient ischemic attack; pioglitazone was associated with increased survival after subsequent stroke but was also associated with weight gain and fractures; meta-analysis by Wallach et al (2020) showed TZDs increase risk for HF

Incretins: non-inferior to placebo for overall risk for CVD; retrospective studies and data from 2016 show no clear association between HF and DPP-4 inhibitors using SUs as controls

GLP-1: Marso et al (2016) found death from CV causes, nonfatal MI, or nonfatal stroke among patients with T2DM was lower with liraglutide; no real difference in HF; another study showed similar results with semaglutide; GLP-1 agonists overall significantly decreases risk for stroke

SGLT2 inhibitors: EMPA-REG study (Zinman et al [2015]) showed empagliflozin in patients with T2DM was associated with improvement in a composite CV outcome, death from any cause, and hospitalization from HF (HHF); HHF decreased ≤1 mo after starting the medication; Neal et al (2017) investigated CV and renal events with canagliflozin; found improvement in CV outcomes; significant reduction in HHF began very quickly after starting the medication; Kosiborod et al (2017) compared SGLT2 inhibitors with other glucose-lowering drugs; SGLT2 inhibitors were associated with a 39% lower incidence of HF, 51% lower rate of all-cause death, and 46% lower rate of combined endpoint of HF and all-cause death; McMurray et al (2019) showed dapagliflozin was associated with improved primary outcome in patients with and without DM; Perkovic et al (2019) showed canagliflozin given to patients with pre-existing renal disease reduced end-stage renal disease, need for dialysis, renal death, worsening albuminuria, and decreasing glomerular filtration rate (GFR); GFR can drop acutely with initiation of therapy, then stabilizes

Side effects of SGLT2 inhibitors: SGLT2 inhibitors are associated with significant risk of urinary tract infection when given to patients with risk factors

Selection of agents for T2DM: in a newly symptomatic patient with high blood glucose levels, metformin or an SGLT2 inhibitor is a poor choice; metformin because the patient can become dehydrated and at greater risk for lactic acidosis; SGLT2 because the patient already has high glucose and is at increased risk for diabetic ketoacidosis (DKA); a SU is a good choice for first drug in a poorly controlled patient; can change to a different drug later; consider insulin for high, out of control blood sugars

SGLT2 inhibitors and DKA: patients with T2DM can develop euglycemic DKA, generally when patients fast before surgery and receive general anesthesia (rare but possible) or when patients are dehydrated already; speaker recommends stopping SGLT2 inhibitors ≥3 to 4 days before any procedure

Readings

American Diabetes Association: 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98-S110; Apolzan JW et al. Long-term weight loss with metformin or lifestyle intervention in the diabetes prevention program outcomes study. Ann Intern Med. 2019;170(10):682-690; Azoulay L and Suissa S. Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies. Diabetes Care. 2017;40(5):706-714; Dormandy et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289; Garber AJ et al. Consensus statement by the American Association of clinical endocrinologists and American College of endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107-139; Kalra S et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015;19(5):577-596. doi:10.4103/2230-8210.163171; Ke C et al. Mortality and cardiovascular risk of sulfonylureas in South Asian, Chinese and other Canadians with diabetes. Can J Diabetes. 2017;41(2):150-155; Kernan WN et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-1331; Kosiborod M et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249-259; Marso SP et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322; Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141; McMurray JJV et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303; Middleton TL et al. Cardiac effects of sulfonylurea-related hypoglycemia. Diabetes Care. 2017;40(5):663-670; Perkovic V et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306; Rosenstock J et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial [published online ahead of print, 2019 Sep 19] [published correction appears in JAMA. 2019 Dec 3;322(21):2138]. JAMA. 2019;322(12):1155-1166; Sanchez-Rangel E, Inzucchi SE. Metformin: Clinical use in type 2 diabetes. Diabetologia. 2017;60(9):1586-1593. doi:10.1007/s00125-017-4336-x; Zinman B et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Rushakoff was recorded virtually at Primary Care Medicine: Principles and Practice, held October 15-17, 2020, and presented by the University of California, San Francisco, School of Medicine, and its Department of Medicine, Division of General Internal Medicine. For information about future CME activities from this sponsor, please visit www.ucsfcme.com. Audio Digest thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM682101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.