Older adults are at high risk for both diabetes and prediabetes, with surveillance data suggesting that half of older adults have the latter (1). The ADA recommends that overweight adults with risk factors—and all adults aged ≥45 years—be screened in the clinical setting every 1–3 years using either an FPG test, A1C, or oral glucose tolerance test. The recommendations are based on substantial indirect evidence for the benefits of early treatment of type 2 diabetes, the fact that type 2 diabetes is typically present for years before clinical diagnosis, and the evidence that signs of complications are prevalent in “newly diagnosed” patients .
The benefits of identification of prediabetes and asymptomatic type 2 diabetes in older adults depend on whether primary or secondary preventive interventions would likely be effective and on the anticipated timeframe of the benefit of interventions versus the patient’s life expectancy. Most would agree that a functional and generally healthy 66-year-old individual should be offered diabetes screening since interventions to prevent type 2 diabetes or the complications of type 2 diabetes would likely be beneficial given the presumption of decades of remaining life. Most would also agree that finding prediabetes or early type 2 diabetes in a 95-year-old individual with advanced dementia would be unlikely to provide benefit.
Prevention or delay of type 2 diabetes
Numerous clinical trials have shown that in high-risk subjects (particularly those with impaired glucose tolerance), type 2 diabetes can be prevented or delayed by lifestyle interventions or by various classes of medications. These trials primarily enrolled middle-aged participants. In the DPP, which is the largest trial to date, ∼20% of participants were aged ≥60 years at enrollment. These participants seemed to have more efficacy from the lifestyle intervention than younger participants, but did not appear to benefit from metformin . Follow-up of the DPP cohort for 10 years after randomization showed ongoing greater impact of the original lifestyle intervention in older participants (49% risk reduction in those aged ≥60 years at randomization vs. 34% for the total cohort) and additional benefits of the lifestyle intervention that might impact older adults, such as reduction in urinary incontinence , improvement in several quality-of-life domains, and improvements in cardiovascular risk factors . Although these results suggest that diabetes prevention through lifestyle intervention be pursued in relatively healthy older adults, the DPP did not enroll significant numbers over the age of 70 years or those with functional or cognitive impairments. Preventive strategies that can be efficiently implemented in clinical settings and in the community have been developed and evaluated , but as yet there has been little focus on older adults in these translational studies.
Interventions to treat diabetes
Glycemic control.
A limited number of randomized clinical trials in type 2 diabetes form the basis of our current understanding of the effects of glucose lowering on microvascular complications, cardiovascular complications, and mortality. While these trials have provided invaluable data and insights, they were not designed to evaluate the health effects of glucose control in patients aged ≥75 years or in older adults with poor health status. There are essentially no directly applicable clinical trial data on glucose control for large segments of the older diabetic patient population.
The UK Prospective Diabetes Study (UKPDS), which provided valuable evidence of the benefits of glycemic control on microvascular complications, enrolled middle-aged patients with newly diagnosed type 2 diabetes, excluding those aged ≥65 years at the time of enrollment . Microvascular benefits persisted during the post-trial follow-up period, and statistically signifi.
After the publication of the main UKPDS results, three major randomized controlled trials (the Action to Control Cardiovascular Risk in Diabetes [ACCORD] trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE] trial, and the Veterans Affairs Diabetes Trial [VADT]) were designed to specifically examine the role of glycemic control in preventing CVD events in middle-aged and older patients with type 2 diabetes. The trials enrolled patients at significantly higher cardiovascular risk than did the UKPDS, with each having a substantial proportion of participants with a prior cardiovascular event, mean age at enrollment in the 60s, and established diabetes (8–11 years). Each of these trials aimed, in the intensive glycemic control arm, to reduce glucose levels to near-normal levels (A1C <6.0 or <6.5%).
The glucose control portion of the ACCORD trial was terminated after approximately 3 years because of excessive deaths in the intensive glucose control arm (. The primary combined outcome of MI, stroke, and cardiovascular death was not significantly reduced. Prespecified subgroup analyses suggested that the disproportionate cardiovascular mortality risk in the intensive glycemic control group was in participants under the age of 65 years as opposed to older participants. However, hypoglycemia and other adverse effects of treatment were more common in older participants.
The ADVANCE trial did not demonstrate excessive deaths attributable to intensive glucose control during a median follow-up of 5 years. While there were no statistically significant cardiovascular benefits, there was a significant reduction in the incidence of nephropathy. In prespecified subgroup analysis of age < or ≥65 years, there was no difference between age-groups for the primary outcome.
Over 5 years of follow-up, the VADT found no statistically significant effect of intensive glucose control on major cardiovascular events or death, but it did find significant reductions in onset and progression of albuminuria . The trial did not have prespecified subgroup analyses by age. Post hoc analyses suggested that mortality in the intensive versus standard glycemic control arm was related to duration of diabetes at the time of study enrollment. Those with diabetes duration less than 15 years had a mortality benefit in the intensive arm, while those with duration of 20 years or more had higher mortality in the intensive arm .
These three trials add to the uncertainty regarding the benefits and risks of more intensive treatment of hyperglycemia in older adults. An ADA position statement surmised that the combination of the UKPDS follow-up study and subset analyses of the later trials ‘‘… suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control, [while] … potential risks of intensive glycemic control may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty” .
Recently, a Japanese trial reported results of a multifactorial intervention versus standard care in about 1,000 patients aged ≥65 years (mean age 72 years). After 6 years, no differences in mortality or cardiovascular events were found, but the intervention’s effect on glycemia was minimal and the number of events was low .
Since randomized controlled trials have not included many older patients typical of those in general practice, it is instructive to observe the relationship between glycemic control and complications in general populations of older diabetic patients. A study from the U.K. General Practice Research Database showed that for type 2 diabetic patients aged ≥50 years (mean age 64 years) whose treatment was intensified from oral monotherapy to addition of other oral agents or insulin, there was a U-shaped association between A1C and mortality, with the lowest hazard ratio for death at an A1C of about 7.5%. Low and high mean A1C values were associated with increased all-cause mortality and cardiac events (34). A retrospective cohort study of 71,092 patients with type 2 diabetes aged ≥60 years evaluated the relationships between baseline A1C and subsequent outcomes (acute nonfatal metabolic, microvascular, and cardiovascular events and mortality). As in the prior study, mortality had a U-shaped relationship with A1C. Compared to risk with A1C <6.0%, mortality risk was lower for A1C between 6.0 and 9.0% and higher at A1C ≥11.0%. Risk of any end point (complication or death) became significantly higher at A1C ≥8.0%. Patterns were generally consistent across age-groups (60–69, 70–79, and ≥80 years) (35).
Diabetes is associated with increased risk of multiple coexisting medical conditions in older adults ranging from CVD to cancer and potentially impacting treatment decisions, such as whether stringent glycemic control would be of net benefit (36,37). A 5-year longitudinal, observational study of Italian patients with type 2 diabetes categorized patients into subgroups of high (mean age 64.3 years [SD 9.5]) and low-to-moderate comorbidity (mean age 61.7 years [SD 10.5]) using a validated patient-reported measure of comorbidity. Having an A1C of ≤6.5 or <7% at baseline was associated with lower 5-year incidence of cardiovascular events in the low-to-moderate comorbidity subgroup, but not in the high comorbidity subgroup, suggesting that patients with high levels of comorbidity may not receive cardiovascular benefit from intensive blood glucose control .
Lipid lowering.
There are no large trials of lipid-lowering interventions specifically in older adults with diabetes. Benefits have been extrapolated from trials of older adults that include but are not limited to those with diabetes and trials of people with diabetes including but not limited to older adults. A statin study in older adults (participants aged 70–82 years) found a 15% reduction in coronary artery disease events with pravastatin. A meta-analysis of 18,686 people with diabetes in 14 trials of statin therapy for primary prevention showed similar 20% relative reductions in major adverse vascular outcomes in those under compared with those over age 65 years (41). Statin trials for secondary prevention of CVD in adults with diabetes have also demonstrated comparable relative reductions in recurrent cardiovascular events and mortality by age-group . Since older patients are at higher risk, absolute risk reductions with statin therapy would be greater in older patients. Cardiovascular prevention with statins, especially secondary benefit, emerges fairly quickly (within 1–2 years), suggesting that statins may be indicated in nearly all older adults with diabetes except those with very limited life expectancy.
The evidence for reduction in major cardiovascular end points with drugs other than statins is limited in any age-group. The ACCORD lipid trial found no benefit of adding fenofibrate to statin therapy , and post hoc analyses suggested that the negative results applied to both those under and those over age 65 years (M. Miller, personal communication). Subgroup analyses of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which suggested some benefit of fenofibrate in people with type 2 diabetes, suggested no benefit in those aged ≥65 years
Blood pressure control.
Multiple trials have investigated the role of treatment of hypertension to reduce the risk of cardiovascular events (17). Benefit for older adults with diabetes has been inferred from the trials of older adults including but not limited to those with diabetes and from the trials of middle- and older-aged adults with diabetes (42). There is consistent evidence that lowering blood pressure from very high levels (e.g., systolic blood pressure [SBP] 170 mmHg) to moderate targets (e.g., SBP 150 mmHg) reduces cardiovascular risk in older adults with diabetes. Selected trials have shown benefit with targets progressively lower, down to SBP <140 mmHg and diastolic blood pressure (DBP) <80 mmHg. The ACCORD-BP trial showed no benefit on the primary outcome (major adverse cardiovascular events) of SBP targets <120 mmHg compared with <140 mmHg, but found a significant reduction in stroke, a secondary outcome. Subgroup analyses of those aged < versus ≥65 years suggested that the stroke benefit may have been limited to the older cohort (M. Miller, personal communication).
Observational analyses of other trial cohorts suggest no benefit to SBP targets more aggressive than <140 mmHg and that low DBP may be a risk factor for mortality in older adults. A post hoc analysis of the cohort of participants with diabetes in the International Verapamil SR-Trandolapril Study (INVEST), whose mean age was ∼65 years, showed that achieved SBP under 130 mmHg was not associated with improved cardiovascular outcomes compared with SBP under 140 mmHg (47). This report validated SBP control under 140 mmHg, as death and cardiovascular events were more likely in subjects whose SBP was over 140 mmHg. A post hoc analysis of the VADT (in which the goal blood pressure was <130/80 mmHg) similarly showed that those whose SBP was ≥140 mmHg had increased mortality, while those at <105 mmHg, 105–129 mmHg, and 130–139 mmHg had equally low mortality rates. For DBP, achieved values <70 mmHg were associated with higher mortality, while those of 70–79 mmHg or >80 mmHg were equally low
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