ADA 2021


Early Combination Therapy for Type 2 Diabetes as per ADA

NEW YORK (Reuters Health) – The 2020 American Diabetes Association, ADA clinical guideline stresses the importance of considering early combination therapy in patients with type 2 diabetes.

“While metformin and therapeutic lifestyle change remain the standard for new-onset diabetes diagnoses, initial combination therapy should be considered in patients presenting with hemoglobin (Hb)A1c levels >1.5 to 2 percentage points above the target, as most singular medications rarely decrease HbA1c concentrations by more than 1 percentage point,” Kacie Doyle-Delgado of St. Mark’s Hospital and St. Mark’s Diabetes Center, in Salt Lake City, told Reuters Health by email.

In a paper in the Annals of Internal Medicine, Dr. Doyle-Delgado and colleagues on the ADA’s Professional Practice Committee summarize the new ADA recommendations related to pharmacologic management of type-2 diabetes and highlight important evidence from recent large trials with cardiovascular and renal outcomes.

According to the guideline, metformin remains the preferred initial pharmacologic agent for treating type 2 diabetes. Still, early combination therapy should be considered in some patients at treatment initiation as a strategy for extending the time to treatment failure.

Early introduction of insulin should be considered for patients who have weight loss, symptoms of hyperglycemia, or very high HbA1c (>10%) or blood glucose (16.7 mmol/L, 300 mg/dL, or higher). But glucagon-like peptide-1 receptor agonists (GLP-1 RA) are preferred over insulin when possible.

For patients who have established atherosclerotic cardiovascular disease or high-risk indicators, established kidney disease, or heart failure, a GLP-1 RA or a sodium-glucose cotransporter-2 (SGLT2) inhibitor demonstrated cardiovascular disease benefit is recommended.

If a patient has heart failure or chronic kidney disease, an SGLT2 inhibitor is recommended. If an SGLT2 inhibitor cannot be used, a GLP-1 RA should be administered.

Treatment selection should be based on individual patient factors, such as cardiovascular comorbid conditions, hypoglycemia risk, impact on weight, cost, the risk for side effects, and patient preferences, the authors say. Medication regimens and medication-taking behavior should be reevaluated every three to six months and adjusted as needed to incorporate these specific factors.

ADA 2020 Changes:

What is your interpretation of the recent international guidelines recommending the use of SGLT-2is in T2DM patients having ASCVD, CV risk, HF, or DKD irrespective of baseline HbA1c?

Prohibit Use of SGLT2-i Therapy, in:

  • Moderate to Severe CKD: Glucose-lowering efficacy lost with eGFR <45mL/min/1.73 m2
  • Pregnant and breast-feeding women: Risk is not known
  • Acute severe stressful conditions (hospitalization / severe illness / surgery): Risk of DKA
  • Insulinopenic conditions, without sufficient insulin replacement: Risk of DKA

Observe Caution in:

  • Risk of volume depletion (frail elderly, concomitant loop diuretics, predisposition to dehydration / renal impairment): Monitor volume and maintain adequate hydration
  • Complicated UTIs: temporary discontinuation is recommended
  • History of recurrent UTIs: Increased risk of UTI; observe caution and counsel accordingly
  • Improper genital hygiene: Risk of Genital Tract Infections; counsel on maintaining hygiene
  • Conditions of fasting: Starvation / Dehydration predisposes to DKA with SGLT2-i
  • Concomitant use with Insulin / Secretagogues: Risk of hypoglycemia; titrate the dose
  • Atherosclerotic CAD and HF are two important manifestations of CVD in T2DM, which account for the majority of deaths in diabetes
  • Personalized medicine approach and guidelines suggest preferential use of SGLT2-i agents in patients with risk of atherosclerotic CVD or HF in diabetes
  • Empagliflozin has demonstrated benefits for CVD events as well as mortality outcomes in patients with Atherosclerotic CVD and T2DM
  • Optimize clinical considerations of risk-benefit for each agent, in the principle of individualized approach for every patient

Although the guideline focuses on pharmacologic treatments, it emphasizes that the mainstay for the initial treatment of type-2 diabetes includes therapeutic lifestyle change.

The clinical guideline also includes detailed algorithms for the overall approach to glucose-lowering medication and the intensification of injectable therapies.

Glycemic Goals

For glycemic goals in older adults, please refer to Section 12, “Older Adults” ( Please refer to Section 13, “Children and Adolescents” ( For glycemic goals in pregnant women, please refer to Section 14, “Management of Diabetes in Pregnancy” ( Overall, regardless of the population being served, the glycemic targets must be woven into the overall patient-centered strategy. For example, in a very young child, safety and simplicity may outweigh the need for perfect control in the short run. Simplification may decrease parental anxiety and build trust and confidence, which could further strengthen glycemic targets and self-efficacy. Similarly, in healthy older adults, there is no empiric need to loosen control. However, the provider needs to work with an individual and should consider adjusting targets or simplifying the regimen if this change is needed to improve safety and adherence.


  • 6.5a An A1C goal for many nonpregnant adults of <7% (53 mmol/mol) without significant hypoglycemia is appropriate. A

  • 6.5b If using ambulatory glucose profile/glucose management indicator to assess glycemia, a parallel goal is a time in the range of >70% with time below range <4% (Fig. 6.1). B

  • 6.6 based on provider judgment and patient preference, achievement of lower A1C levels than the goal of 7% may be acceptable and even beneficial if it can be achieved safely without significant hypoglycemia or other adverse effects of treatment. C

  • 6.7 Less stringent A1C goals (such as <8% [64 mmol/mol]) may be appropriate for patients with limited life expectancy or where the harms of treatment are greater than the benefits. B

  • 6.8 Reassess glycemic targets over time based on the criteria in Fig. 6.2 and older adults (Table 12.1). E

Figure 6.2

Patient and disease factors are used to determine optimal glycemic targets. Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts. A1C 7% = 53 mmol/mol. Adapted with permission from Inzucchi et al. (59).

A1C and Microvascular Complications

Hyperglycemia defines diabetes, and glycemic control is fundamental to diabetes management. The Diabetes Control and Complications Trial (DCCT) (25), a prospective randomized controlled trial of intensive (mean A1C about 7% [53 mmol/mol]) versus standard (mean A1C about 9% [75 mmol/mol]) glycemic control in patients with type 1 diabetes, showed definitively that better glycemic control is associated with 50–76% reductions in rates of development and progression of microvascular (retinopathy, neuropathy, and diabetic kidney disease) complications. Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (28,29) demonstrated persistence of these microvascular benefits over two decades even though the glycemic separation between the treatment groups diminished and disappeared during follow-up.

The Kumamoto Study (30) and UK Prospective Diabetes Study (UKPDS) (31,32) confirmed that intensive glycemic control significantly decreased rates of microvascular complications in patients with short-duration type 2 diabetes. Long-term follow-up of the UKPDS cohorts showed enduring effects of early glycemic control on most microvascular complications (33).

Therefore, achieving A1C targets of <7% (53 mmol/mol) has been shown to reduce microvascular complications of type 1 and type 2 diabetes when instituted early in the course of the disease (1,34). Epidemiologic analyses of the DCCT (25) and UKPDS (35) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from feeble control to fair/good control. These analyses also suggest that further lowering of A1C from 7% to 6% [53 mmol/mol to 42 mmol/mol] is associated with further reduction in the risk of microvascular complications. However, the absolute risk reductions become much smaller. These findings imply no need to de-intensify therapy for an individual with an A1C between 6% and 7% and a low hypoglycemia risk with a long life expectancy. There are now newer agents that do not cause hypoglycemia, making it possible to maintain glucose control without the risk of hypoglycemia (see Section 9 “Pharmacologic Approaches to Glycemic Treatment,”

Given the substantially increased risk of hypoglycemia in type 1 diabetes and polypharmacy in type 2 diabetes, the risks of lower glycemic targets may outweigh the potential benefits of microvascular complications. Three landmark trials (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], and Veterans Affairs Diabetes Trial [VADT]) were conducted to test the effects of near normalization of blood glucose on cardiovascular outcomes in individuals with long-standing type 2 diabetes and either known cardiovascular disease (CVD) or high cardiovascular risk. These trials showed that lower A1C levels were associated with reduced onset or progression of microvascular complications (3638).

The concerning mortality findings in the ACCORD trial (39), discussed below, and the relatively intense efforts required to achieve near euglycemia should also be considered when setting glycemic targets for individuals with long-standing diabetes, such as those studied in ACCORD, ADVANCE, and VADT. Findings from these studies suggest caution is needed in treating diabetes aggressively to near-normal A1C goals in people with long-standing type 2 diabetes with or at significant risk of CVD. These landmark studies need to be considered with an important caveat; glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors were not approved at the time of these trials. As such, these agents with established cardiovascular and renal benefits appear to be safe in this group of high-risk patients. Clinical trials examining these agents for cardiovascular safety were not designed to test higher versus lower A1C; therefore, beyond post hoc analysis of these trials, we do not have evidence that it is the glucose-lowering by these agents that confers the CVD and renal benefit (40). As such, based on physician judgment and patient preferences, select patients, especially those with little comorbidity and long life expectancy, may benefit from adopting more intensive glycemic targets if they can achieve them safely without hypoglycemia or significant therapeutic burden.

A1C and Cardiovascular Disease Outcomes

Cardiovascular Disease and Type 1 Diabetes

CVD is a more common cause of death than microvascular complications in populations with diabetes. There is evidence for a cardiovascular benefit of intensive glycemic control after long-term follow-up of cohorts treated early in the course of type 1 diabetes. In the DCCT, there was a trend toward a lower risk of CVD events with intensive control. In the 9-year post-DCCT follow-up of the EDIC cohort, participants previously randomized to the intensive arm had a significant 57% reduction in the risk of nonfatal myocardial infarction (MI), stroke, or cardiovascular death compared with those previously randomized to the standard arm (41). The benefit of intensive glycemic control in this cohort with type 1 diabetes has been shown to persist for several decades (42) and to be associated with a modest reduction in all-cause mortality (43).

Cardiovascular Disease and Type 2 Diabetes

In type 2 diabetes, there is evidence that more intensive treatment of glycemia in newly diagnosed patients may reduce long-term CVD rates. In addition, data from the Swedish National Diabetes Registry (44) and the Joint Asia Diabetes Evaluation (JADE) demonstrate greater proportions of people with diabetes being diagnosed at <40 years of age and a demonstrably increased burden of heart disease and years of life lost in people diagnosed at a younger age (4548). Thus, to prevent both microvascular and macrovascular complications of diabetes, there is a major call to overcome therapeutic inertia and treat to target for an individual patient (47,49). During the UKPDS, there was a 16% reduction in CVD events (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm that did not reach statistical significance (P = 0.052), and there was no suggestion of benefit on other CVD outcomes (e.g., stroke). Similar to the DCCT/EDIC, after 10 years of observational follow-up, those originally randomized to intensive glycemic control had significant long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy) and all-cause mortality (13% and 27%, respectively) (33).

ACCORD, ADVANCE, and VADT suggested no significant reduction in CVD outcomes with intensive glycemic control in participants followed for shorter durations (3.5–5.6 years) and who had more advanced type 2 diabetes than UKPDS participants. All three trials were conducted in relatively older participants with a longer known duration of diabetes (mean duration 8–11 years) and either CVD or multiple cardiovascular risk factors. The target A1C among intensive-control subjects was <6% (42 mmol/mol) in ACCORD, <6.5% (48 mmol/mol) in ADVANCE, and a 1.5% reduction in A1C compared with control subjects in VADT, with achieved A1C of 6.4% vs. 7.5% (46 mmol/mol vs. 58 mmol/mol) in ACCORD, 6.5% vs. 7.3% (48 mmol/mol vs. 56 mmol/mol) in ADVANCE, and 6.9% vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) in VADT. Details of these studies are reviewed extensively in the joint ADA position statement, “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials” (50).

The glycemic control comparison in ACCORD was halted early due to an increased mortality rate in the intensive compared with the standard treatment arm (1.41% vs. 1.14% per year; hazard ratio 1.22 [95% CI 1.01–1.46]), with a similar increase in cardiovascular deaths. Analysis of the ACCORD data did not identify a clear explanation for the excess mortality in the intensive treatment arm (39).

Longer-term follow-up has shown no evidence of cardiovascular benefit or harm in the ADVANCE trial (51). The end-stage renal disease rate was lower in the intensive treatment group over follow-up. However, a 10-year follow-up of the VADT cohort (52) showed a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality. Heterogeneity of mortality effects across studies was noted, reflecting differences in glycemic targets, therapeutic approaches, and, importantly, population characteristics (53).

Mortality findings in ACCORD (39) and subgroup analyses of VADT (54) suggest that the potential risks of intensive glycemic control may outweigh its benefits in higher-risk patients. In all three trials, severe hypoglycemia was significantly more likely in randomly assigned participants to the intensive glycemic control arm. Those patients with a long duration of diabetes, a known history of hypoglycemia, advanced atherosclerosis, or advanced age/frailty may benefit from less aggressive targets (55,56).

As discussed further below, severe hypoglycemia is a potent marker of high absolute risk of cardiovascular events and mortality (57). Providers should be vigilant in preventing hypoglycemia and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved. As discussed in Section 9, “Pharmacologic Approaches to Glycemic Treatment” (, the addition of specific (SGLT2) inhibitors or GLP-1 receptor agonists that have demonstrated CVD benefit is recommended for use in patients with established CVD, chronic kidney disease, and heart failure. As outlined in more detail in Section 9, “Pharmacologic Approaches to Glycemic Treatment” ( and Section 10 “Cardiovascular Disease and Risk Management” (, the cardiovascular benefits of SGLT2 inhibitors or GLP-1 receptor agonists are not dependent upon A1C lowering; therefore, initiation can be considered in people with type 2 diabetes and CVD independent of the current A1C or A1C goal or metformin therapy. Based on these considerations, the following two strategies are offered (58):

  • 1. If already on dual therapy or multiple glucose-lowering therapies and not on an SGLT2 inhibitor or GLP-1 receptor agonist, consider switching to one of these agents with proven cardiovascular benefit.

  • 2. Introduce SGLT2 inhibitors or GLP-1 receptor agonists in patients with CVD at A1C goal (independent of metformin) for cardiovascular benefit, independent of baseline A1C or individualized A1C target.

Setting and Modifying A1C Goals

Numerous factors must be considered when setting glycemic targets. The ADA proposes general targets appropriate for many patients but emphasizes the importance of individualization based on key patient characteristics. Glycemic targets must be individualized in the context of shared decision-making to address the needs and preferences of each patient and the individual characteristics that influence risks and benefits of therapy for each patient to optimize patient engagement and self-efficacy.

The factors to consider in individualizing goals are depicted in Fig. 6.2. This figure is not designed to be applied rigidly but to be used as a broad construct to guide clinical decision-making (59) and engage in shared decision-making in people with type 1 and type 2 diabetes. More stringent targets may be recommended if they can be achieved safely and with an acceptable burden of therapy and if life expectancy is sufficient to reap the benefits of stringent targets. Less stringent targets (A1C up to 8% [64 mmol/mol]) may be recommended if the patient’s life expectancy is such that the benefits of an intensive goal may not be realized or if the risks and burdens outweigh the potential benefits. Severe or frequent hypoglycemia is an absolute indication for modifying treatment regimens, including setting higher glycemic goals.

Diabetes is a chronic disease that progresses over decades. Thus, a goal that might be appropriate for an individual early in the course of their diabetes may change over time. Newly diagnosed patients and/or those without comorbidities that limit life expectancy may benefit from intensive control proven to prevent microvascular complications. Both DCCT/EDIC and UKPDS demonstrated metabolic memory, or a legacy effect, in which a finite period of intensive control yielded benefits that extended for decades after that control ended. Thus, a finite period of intensive control to near-normal A1C may yield enduring benefits even if control is subsequently deintensified as patient characteristics change. Over time, comorbidities may emerge, decreasing life expectancy and decreasing the potential to reap benefits from intensive control. Also, with a longer duration of disease, diabetes may become more difficult to control, increasing the risks and burdens of therapy. Thus, A1C targets should be reevaluated over time to balance the risks and benefits as patient factors change.

Recommended glycemic targets for many nonpregnant adults are shown in Table 6.3. The recommendations include blood glucose levels that appear to correlate with the achievement of an A1C of <7% (53 mmol/mol). Pregnancy recommendations are discussed in more detail in Section 14, “Management of Diabetes in Pregnancy” (

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