Metabolic syndrome and newonset diabetes

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The prevalence of obesity, the metabolic syndrome, and frank diabetes has doubled in the USA over the past decade. With more than 60% of adults and 30% of children classified as overweight or obese, the USA has become the fattest nation on earth. Approximately half of all overweight individuals have insulin resistance and 25% of the population of the USA has multiple risk factors for cardiovascular disease. Cardiovascular risk factors tend to cluster, and insulin resistance or diabetes, obesity, and hypertension are common in the same patient. Ever since the pioneering observation of Colin Dollery's team [59,60] more than 20 years ago, a variety of studies have documented that long-term diuretic therapy, particularly when combined with a beta-blocker, diminishes glucose tolerance and increases the risk of new-onset diabetes. Conversely, as has been revealed in more recent trials, treatment with antihypertensive drugs, such as blockers of the RAS or calcium antagonists, appears to decrease this risk (Figure 25).

The ALPINE study

The recent Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE) study was designed to compare the effects of antihypertensive therapy on glucose metabolism in almost 400 patients with uncomplicated hypertension who had never been treated [62]. Patients were randomized to either an ARB (with addition of calcium antagonist, if needed) or a thiazide diuretic (and a beta-blocker, if needed). After only 1 year of follow-up, 18 patients in the diuretic arm reached diagnostic criteria of the metabolic syndrome and nine had developed frank diabetes. The corresponding numbers in the ARB arm were five and one, respectively.

Meta-analysis of effect of antihypertensive drugs on risk of new-onset diabetes

ARB--

0.57 (0.46-0.72) p<0.0001

ACE inhibitor - -

0.67 (0.56-0.80) p<0.0001

CCB - -

0.75 (0.62-0.90) p=0.002

Placebo - -

0.77 (0.63-0.94) p=0.009

ß-blocker - -

0.90 (0.75-1.09) p=0.30

Diuretic I

1

0.50 0.70 0.90

1.26

Odds ratio of incident diabetes

Incoherence=0.000017

Figure 25 Meta-analysis of effect of antihypertensive drugs on risk of new-onset diabetes.

Results of network meta-analysis of 22 clinical trials. Trials included 143,153 patients. Initial diuretic used as referent agent. Size of squares (representing the point estimate for each class of antihypertensive drugs) is proportional to number of patients who developed incident diabetes. Horizontal lines indicate 95% confidence interval (CI). Odds ratios to the left of the vertical line at unity denote a protective effect (compared with initial diuretic). Individual pair-wise comparisons between diuretic vs beta-blocker (p=0.30), placebo vs calcium channel blocker (CCB) (p=0.72), angiotensin-converting enzyme (ACE) inhibitor vs angiotensin receptor blocker (ARB) (p=0.16) did not achieve significance (p<0.05). Reproduced with permission from Elliott [61].

Figure 25 Meta-analysis of effect of antihypertensive drugs on risk of new-onset diabetes.

Results of network meta-analysis of 22 clinical trials. Trials included 143,153 patients. Initial diuretic used as referent agent. Size of squares (representing the point estimate for each class of antihypertensive drugs) is proportional to number of patients who developed incident diabetes. Horizontal lines indicate 95% confidence interval (CI). Odds ratios to the left of the vertical line at unity denote a protective effect (compared with initial diuretic). Individual pair-wise comparisons between diuretic vs beta-blocker (p=0.30), placebo vs calcium channel blocker (CCB) (p=0.72), angiotensin-converting enzyme (ACE) inhibitor vs angiotensin receptor blocker (ARB) (p=0.16) did not achieve significance (p<0.05). Reproduced with permission from Elliott [61].

The VALUE study

In the VALUE study, more than 15,000 patients with hypertension and one or more additional risk factor were randomized to either amlodipine or valsartan [32].

Investigators found that new-onset diabetes was 23% less common in the patients treated with valsartan than in those treated with amlodipine, despite the fact that BP control was significantly better with amlodipine throughout the study. These results have to be interpreted in the context of the ALLHAT study [43], in which the risk of new-onset diabetes was significantly lower with amlodipine than with chlorthalidone, but not as low as with lisinopril. Of note, however, patients who were randomized to amlodipine had significantly greater hypokalemia than patients who were randomized to valsartan. Hypokalemia can impair glucose tolerance by interfering with insulin release from the pancreas. Such a sequence of events was originally proposed by Conn [63] to explain the high risk of diabetes in patients with primary aldosteronism. These findings were subsequently confirmed by the same group in patients with islet cell tumors. Helderman et al. [64] reported that glucose intolerance associated with thiazide diuretics could be entirely avoided if whole-body potassium balance was maintained. Thus, the higher risk of de novo diabetes in the amlodipine arm could possibly be explained by the greater prevalence of hypokalemia.

The ALLHAT trial

In the ALLHAT study [43], about 10% ofthe total study population ofpatients developed new-onset diabetes during the 4- to 6-year duration of the study. Of note, the risk of becoming diabetic was between 40% and 65% higher in patients on chlorthalidone-based therapy than in patients on lisinopril-based therapy, and between 18% and 30% higher in patients on chlorthalidone than in those on amlodipine.

The ALLHAT investigators [43] reassuringly state that, "Overall, these metabolic differences did not translate into more cardiovascular events or into higher all-cause mortality in the chlorthalidone group." That this statement was used almost verbatim by the authors of the JNC 7 report [2] is perhaps not surprising given that more than half of them were ALLHAT investigators. However, these reassuring words may strike the practicing physician as slightly myopic given that the follow-up in ALLHAT after the diagnosis of diabetes was 2-4 years. Antihypertensive therapy is most often lifelong and a follow-up lasting a few years is unlikely to give us any information as to the cardiovascular morbidity and mortality related to thiazide diuretic-associated diabetes.

Long-term follow-up

The recent thorough study of Verdecchia et al. [65] has thrown some light on this issue. The authors report up to 16 years of follow-up of almost 800 initially untreated hypertensive patients, 6.5% of whom had diabetes at the onset, and 5.8% ofwhom developed new-onset diabetes throughout the study. The fasting blood sugar at entry, as well as diuretic treatment on follow-up, were independent, powerful predictors of new-onset diabetes (p<0.0001, and p<0.004, respectively). Most importantly, compared with individuals who never developed diabetes, the risk for cardiovascular disease during the follow-up was very similar in patients who developed diabetes (odds ratio [OR] 2.92, 95% confidence interval [CI]: 1.33-6.41; p=0.007) and in the group that had pre-existing diabetes (OR 3.57, 95% CI: 1.65-7.73; p=0.001). Patients with new-onset diabetes, and those with a prior diagnosis of diabetes, were almost three times as likely to develop subsequent cardiovascular disease than those who remained free of diabetes. These provocative findings not only show, again, that antihypertensive therapy with a thiazide diuretic alone or, if needed, in combination with a beta-blocker confers a substantial risk of new-onset diabetes, but also more importantly that patients who have become diabetic will suffer all the adverse sequelae of this disease. Alderman et al. [66], in a study of almost 7000 patients, showed that cardiovascular disease increased in hypertensive diuretic users who developed hyperglycemia even when BP was well controlled. The authors stated, "Cardiovascular disease incidence has a direct dose-response relation with diuretic used with frequent users having the highest rate" [66]. Conceivably, the combination of a diuretic and an ACE inhibitor may confer a lesser risk of new-onset diabetes. At least in one small short-term study, ACE inhibitors seemed to prevent the metabolic deleterious effect of the diuretic thiazide [66]. By preventing hypokalemia RAS blockers may lower the risk of diuretic-induced metabolic adverse events.

Antihypertensive therapy in the diabetic patient

The above considerations make it clear that the patient with diabetes and hypertension benefits from blockade of the RAS more than from any other pharmacologic intervention. Clearly, therefore, blockers of the RAS are a cornerstone in antihypertensive therapy for the diabetic patient. Unfortunately, many patients with diabetes and hypertension are black or have hyporeninemic hypoaldosteronism. In these patient groups, the antihypertensive efficacy of ACE inhibitors and ARBs is blunted. However, despite lowering BP less well, ACE inhibitors, and probably ARBs, still have distinct nephroprotective and possibly cardioprotective effects. Calcium antagonists have been shown to exert impressive morbidity and mortality benefits in the patient with diabetes and hypertension and, therefore, should be added as second-line agents. Dihydropyridine calcium antagonists may lower BP somewhat more than the nondihydropyridines, although the latter are preferred in the diabetic patient because of their synergistic effect on proteinuria when given with an ACE inhibitor. Low-dose thiazide diuretics are acceptable, preferentially as third-line agents. In combination with a RAS blocker, the diabetogenic effect of thiazide diuretics is relatively small. Traditional beta-blockers should be used sparingly in diabetic patients, as these drugs have been shown to increase the risk of diabetes and also to cause systematic weight gain. Of note, carvedilol seems to be void of these effects and, therefore, is the beta-blocker of choice in patients with diabetes.

In patients with diabetes post-MI, the benefits of the beta-blocker clearly outweigh its potential negative effect.

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